Naproxen Tablets Bp 500mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Naproxen Tablets B.P. 500mg
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
500mg Naproxen B.P
For the full list of excipients, see section 6.1
3. PHARMACEUTICAL FORM
Uncoated tablets
Yellow, oval-shaped tablets with marking ‘N500’ on one face and ‘PV’ on the other face.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Adults:
Naproxen is indicated in rheumatoid arthritis, osteoarthrosis (degenertive arthritis), Ankylosing spondylitis, acute gout, acute musculoskeletal disorders, (such as pain and strains, direct trauma lumbosacral-pain cervical spondylitis, tenosynovitis and fibrositis) and dysmenorrhoea.
Children:
For Juvenile rheumatoid arthritis.
4.2 Posology and method of administration:
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (See section 4.4).
Posology:
Adults-
For rheumatoid arthritis, osteoarthrosis and ankylosing spondilitis:
The usual dose is 500mg tolg a day taken in two doses at 12 hour intervals or alternatively, as a single administration.
In the following cases a loading dose of 750mg or lg per day for the acute phase is recommended:
(a) In patients reporting severe night time pain and /or morning stiffness.
(b) In patients being switched to naproxen from a high dose of another antirheumatic compound.
(c) In osteoarthritis where pain is the predominant symptom.
For acute gout 750mg at once then 250mg every 8 hours until the attack has passed.
For acute musculoskeletal disorders and Dysmenorrhoea 500mg initially followed by 250mg at 6-8 hour intervals as needed, with a maximum daily dose, after the first day, of 1250mg.
Children (over 5 years)- For juvenile rheumatoid arthritis in children over 5 years of age, the usual dosage are 10mg/kg body weight daily taken in two doses at 12hour intervals.
Naproxen is not recommended for use in any other indication in children under 16 years of age.
Elderly: Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. The implication of this finding for Naproxen dosing is unknown. As with other drugs used in the elderly it is prudent to use the lowest effective dose and for the shortest duration possible as elderly patients are more prone to adverse events. The patient should be monitored regularly for GI bleeding during NSAID therapy. For the effect of reduced elimination in the elderly refer to Section 4.4.
Renal/hepatic impairment: A lower dose should be considered in patients with renal or hepatic impairment. Naproxen is contraindicated in patients with baseline creatinine clearance less than 30 ml/minute because accumulation of naproxen metabolites has been seen in patients with severe renal failure or those on dialysis (see section 4.3).
Treatment should be reviewed at regular intervals and discontinued if no benefit is seen or intolerance occurs.
Method of Administration:
For oral administration: To be taken preferably with or after food.
4.3 Contraindications
Hypersensitivity to naproxen, naproxen sodium, or any of the constituents.
NSAIDs are contraindicated in patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, nasal polyps, angioedema or urticaria) in response to Naproxen, aspirin, or other nonsteroidal anti-inflammatory drugs.
Severe hepatic, renal and cardiac failure (see section 4.4-special warnings and precautions for use). These reactions have the potential of being fatal. Severe anaphylactic-like reactions to naproxen have been reported in such patients.
During the last trimester of pregnancy (See section 4.6-pregnancy and lactation)
History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.
Active or history of recurrent peptic ulcer/haemorrahage (two or more distinct episodes of proven ulceration or bleeding)
In principle, naproxen must not be administered to patients with gastrointestinal ulcerations, congestive gastritis or atrophic gastritis, gastrointestinal bleeding or other bleeding such as cerebrovascular bleeding.
Haemorrhoids or predisposition to rectal bleeding.
4.4 Special warnings and precautions for use
In all patients:
Undesirable effects may be minimised by using the minimum effective dose for the shortest possible duration necessary to control symptoms (see section 4.2 and GI and cardiovascular risks below).
Patients treated with NSAIDs long-term should undergo regular medical supervision to monitor for adverse events.
Other NSAIDs:
Use with concomitant NSAIDs including cyclo-oxygenase 2 specific inhibitors (See section 4.5 interactions).
Elderly:
The elderly and/or debilitated patients are particularly susceptible to the adverse effects of NSAIDs especially gastrointestinal bleeding and perforation, which may be fatal (See section 4.2-Posology and administration) Prolonged use of NSAIDs in these patients is not recommended. Where prolonged therapy is required patients should be reviewed regularly.
Severe gastrointestinal side effects may occur in patients who use prostaglandin synthetase inhibitors. The risk of developing gastrointestinal ulcers or bleeding increases with the duration of use and dose of naproxen. This risk is not limited to a specific patient population, but the elderly and debilitated individuals exhibit poorer tolerance to gastrointestinal ulceration or bleeding than others. The majority of fatal gastrointestinal effects attributed to prostaglandin synthetase inhibitors occurred in this population.
The antipyretic and anti-inflammatory activities of Naproxen may reduce fever and inflammation, thereby diminishing their utility as diagnostic signs.
Respiratory disorders:
Caution is required if administered to patients suffering from, or with a previous history of, bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in such patients.
Cardiovascular, Renal and Hepatic Impairment:
There have been reports of impaired renal function, renal failure, acute interstitial nephritis, haematuria, proteinuria, renal papillary necrosis and occasionally nephrotic syndrome associated with naproxen.
Renal failure linked to reduced prostaglandin production- The administration of NSAIDs may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure. Patients at great risk of this reaction are those with impaired renal function, cardiac impairment, and liver dysfunction, especially in the case of long-term treatment, those taking diuretic, angiotensin converting enzyme inhibitors, angiotensin-II receptor antagonists and the elderly. Care must also be taken to ensure adequate diuresis. Renal function should be monitored in these patients (See also section 4.3-
Contraindication) Caution in patients with history of hypertension and/or heart failure as fluid retention and oedema have been reported in association with NSAID therapy.
Use in patients with impaired renal function- As naproxen is eliminated mainly (95%) by urinary excretion it should be used with great caution in patient with impaired renal function. Monitoring of serum creatinine and/ or creatinine clearance is advised and patients should be adequately hydrated. Naproxen is contraindicated in patients having a baseline creatinine clearance of less than 30ml/minute.
Haemodialysis does not decrease the plasma concentration of naproxen because of the high degree of protein binding.
Certain patients, specifically those whose renal blood flow is compromised, such as in extracellular volume depletion, cirrhosis of the liver, sodium restriction, congestive heart failure, and pre-existing renal disease, should have renal function assessed before and during Naproxen therapy. Some elderly patients in whom impaired renal function may be expected, as well as patients using diuretics, may also fall within this category. A reduction in daily dosage should be considered to avoid the possibility of excessive accumulation of naproxen metabolites in these patients.
Use in patients with impaired liver function- Care should also be exercised in patients with hepatic insufficiency.
Caution is advised when high doses of naproxen are administered to elderly patients, because there are indications that the quantity of non-protein-bound naproxen increases in such patients. Since naproxen has an anti-inflammatory, analgesic and antipyretic effect, certain symptoms of infection can therefore be masked.
Chronic alcoholic liver disease and probably other forms of cirrhosis reduce the total plasma concentration of naproxen but the plasma concentration of unbound naproxen is increased. The implication in dosing is unknown but it is prudent to use the lowest effect dose of naproxen. Naproxen should be avoided in patients who are breast -feeding.
As with other non-steroidal anti-inflammatory drugs, elevations of one or more liver function tests may occur. Hepatic abnormalities may be the result of hypersensitivity rather than direct toxicity. Severe hepatic reactions, including jaundice and hepatitis (some cases of hepatitis have been fatal) have been reported with this drug as with other non-steroidal anti-inflammatory drugs. Cross reactivity has been reported.
Gastrointestinal bleeding, ulceration and perforation:
GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events.
The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), when used with alcohol, in smoking and in the elderly. These patients should commence treatment on the lowest dose available.
Patients with a history of GI toxicity, particular when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.
Caution should be advised in patients receiving concomitant medications, which could increase the risk of gastrotoxicity or bleeding, such as Corticosteroids, or anticoagulant such as warfarin or anti-platelet agents such as aspirin, and selective serotonin reuptake inhibitors(SSRI’s) (See section 4.5 Interactions). If a corticosteroid is replaced by naproxen and the substitution occurs partially or fully, the usual precautions which come into consideration when discontinuing corticosteroid treatment should be applied.
When GI bleeding or ulceration occurs in patients receiving naproxen, the treatment should be withdrawn.
NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn’s disease) as these conditions may be exacerbated (See section 4.8 undesirable effects).
Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose aspirin, or other drugs likely to increase gastrointestinal risk (see section 4.5).
Haematological
Patients who have coagulation disorders or are receiving drug therapy that interferes with haemostasis should be carefully observed if naproxen-containing products are administered.
Patients at high risk of bleeding or who use coumarin derivatives or heparin alongside naproxen have an increased risk of bleeding. The benefits in that case should be weighed up against the risks. In any case concomitant use of naproxen with a high dose of heparin (or derivatives thereof) is not recommended.
Naproxen decreases platelet aggregation and prolongs bleeding time. This effect should be kept in mind when bleeding times are determined.
Anaphylactic (anaphylactoid) reactions
Hypersensitivity reactions may occur in susceptible individuals. Anaphylactic (anaphylactoid) reactions may occur both in patients with and without a history of hypersensitivity or exposure to aspirin, other non-steroidal anti-inflammatory drugs or naproxen-containing products. They may also occur in individuals with a history of angio-oedema, bronchospastic reactivity (e.g. asthma), rhinitis and nasal polyps.
Anaphylactoid reactions, like anaphylaxis, may have a fatal outcome.
Steroids
If steroid dosage is reduced or eliminated during therapy, the steroid dosage should be reduced slowly and the patients must be observed closely for any evidence of adverse effects, including adrenal insufficiency and exacerbation of symptoms of arthritis.
Ocular effects
Studies have not shown changes in the eye attributable to naproxen administration. In rare cases, adverse ocular disorders including papillitis, retrobulbar optic neuritis and papilloedema, have been reported in users of NSAIDs including naproxen, although a cause-and-effect relationship cannot be established; accordingly, patients who develop visual disturbances during treatment with naproxen-containing products should have an ophthalmological examination.
Cardiovascular and cerebrovascular effects
Appropriate monitoring and advice are-required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.
Mild peripheral oedema has been observed in a few patients receiving naproxen. Although sodium retention has not been reported in metabolic studies, it is possible that patients with questionable or compromised cardiac function may be at a greater risk when taking Naproxen.
Clinical trial and epidemiological data suggest that use of coxibs and some NSAIDs (Particularly at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Although data suggest that the use of naproxen (1000 mg daily) may be associated with a lower risk, some risk cannot be excluded.
Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with naproxen after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, and smoking).
Dermatological
Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens- Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see 4.8). Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reactions occurring in the majority of cases within the first month of treatment. Naproxen should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity. If the skin becomes delicate or in the event of blistering or other symptoms of pseudoporphyria, treatment should be discontinued and the patient should be carefully monitored.
Combination with other NSAIDs including cyclooxygenase-2 selective inhibitors
The combination of naproxen-containing products and other NSAIDs, including cyclooxygenase-2 selective inhibitors, is not recommended, because of the cumulative risks of inducing serious NSAID-related adverse events.
SLE and mixed connective tissue disease:
In patients with systematic lupus erythematosus (SLE) and mixed connective tissue disorders there may be increased risk of aseptic meningitis (See section 4.8- undesirable effects).
Female fertility:
The use of Naproxen, as with any drug known to inhibit cyclooxygenase/prostaglandin synthesis, may impair female fertility and is not recommended in woman attempting to conceive. In woman who have difficulties conceive. In woman who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of naproxen should be considered.
Interference in tests:
It is suggested that Naproxen therapy be temporarily discontinued 48 hours before adrenal function tests are performed, because naproxen may artifactually interfere with some tests for 17-ketogenic steroids. Similarly, naproxen may interfere with some assays of urinary 5-hydroxyindoleacetic acid. Sporadic abnormalities in laboratory tests (e.g. liver function test) have occurred in patients on naproxen therapy, but no definite trend was seen in any test indicating toxicity.
Contains Lactose:
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
Antacid or colestyramine: Concomitant administration of antacid or colestyramine can delay the absorption of naproxen but does not affect its extent. Naproxen should be taken at least one hour before or four to six hours after colestyramine.
Food: Concomitant administration of food can delay the absorption of naproxen, but does not affect its extent.
Other analgesics including cyclooxygenase-2 selective inhibitors: Avoid concomitant use of two or
more NSAIDs (including aspirin) as this may increase the risk the adverse effects (See section 4.4)
Anti-hypertensives: Reduced anti-hypertensive effects. Concomitant administration of naproxen with beta blockers may reduce their antihypertensive effect and may increase the risk of renal impairment associated with the use of ACE inhibitors or angiotensin II receptor antagonists, especially in patients with pre-existing poor renal function (see section 4.4).
Diuretics: Caution is advised when Naproxen is co-administered with diuretics as there can be a reduced diuretic effect. The natriuretic effect of furosemide has been reported to be inhibited by some drugs of this class. Diuretics can increase the risk of nephrotoxicity of NSAIDs.
Cardiac glycosides; NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside level.
Lithium: Inhibition of renal lithium clearance leading to increases in plasma lithium concentrations has also been reported following administration of these agents.
Methotrexate: Decreased elimination of methotrexate. Caution is advised when methotrexate is administered concurrently because of the possible enhancement of its toxicity, since naproxen, among other non-steroidal anti-inflammatory drugs, has been reported to reduce the tubular secretion of methotrexate in an animal model.
Ciclosporin: Increased risk of nephrotoxicity.
Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.
Corticosteroids: Increased risk of GI bleeding or ulceration (See section 4.4- special warnings and precautions for use)
Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIsj: Increased risk of GI bleeding (see section 4.4 - Special warning and precautions for use) when anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs) are combined with NSAIDs.
Anti-coagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin or heparin (See section 4.4-special warnings and precautions for use).
Effect of high plasma protein binding of Naproxen on other drugs:
Due to the high plasma protein binding of naproxen, patients simultaneously receiving hydantoins, anticoagulants, other NSAIDs, aspirin or a highly protein-bound sulphonamide should be observed for signs of overdosage of these drugs. Patients simultaneously receiving Naproxen and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required. No interactions have been observed in clinical studies with naproxen and anticoagulants or sulphonylureas, but caution is nevertheless advised since interaction has been seen with other non-steroidal agents of this class.
Probenecid: Probenecid given concurrently increases naproxen plasma levels and extends its half-life considerably.
Zidovudine: There is an increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV(+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.
Bisphosphonates: concomitant use of bisphosphonates and NSAIDs may increase the risk of gastric mucosal damage.
Quinolone antibiotics: Animal data indicates that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolone may have an increased risk of developing convulsions.
Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.
Test and Assays: It is suggested that Naproxen therapy be temporarily discontinued 48 hours before adrenal function tests are performed, because naproxen may interfere with some tests for 17- ketogenic steroids and some assays for 5-hydroxyindoleacetic acid.
4.6 Pregnancy and lactation:
Pregnancy:
Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a
prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1%, up to approximately 1.5 %. The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period. During the first and second trimester of pregnancy, Naproxen should not be given unless clearly necessary. If Naproxen is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.
During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose
the foetus to:
- cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
- renal dysfunction, which may progress to renal failure with oligo-hydroamniosis; the mother and the neonate, at the end of pregnancy, to:
- possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses.
- inhibition of uterine contractions resulting in delayed or prolonged labour. Consequently, Naproxen is contraindicated during the third trimester of pregnancy. Labour and delivery:
Naproxen containing products are not recommended in labour and delivery because, through its prostaglandin synthesis inhibitory effect, naproxen may adversely affect foetal circulation and inhibit contractions, with an increased bleeding tendency in both mother and child.
Lactation:
In the limited studies so far available, NSAIDs can appears in the breast milk in very low concentration. NSAIDSs should, if possible, be avoided when breastfeeding.
(See section 4.4 Special warnings and precautions for use), regarding female fertility.
4.7 Effects on ability to drive and use machines
Undesirable effects such as dizziness, drowsiness, vertigo, fatigue and visual disturbances or depression are possible after taking NSAIDs. If affected, patients should not drive or operate machinery.
Undesirable effects
4.8
Gastrointestinal: The most commonly observed adverse events are gastrointestinal in nature. Inflammation, peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur (See section4.4) Nausea, vomiting, flatulence, constipation, heartburn, dry mouth, throat irritation, decreased appetite, epigastric distress, diarrhoea, dyspepsia, abdominal pain, melaenia, haematemesis, stomatitis, exacerbation of ulcerative colitis and Crohn's disease (see section 4.4 -Special warning and precautions for use), oesophagitis and gastrointestinal haemorrhage have been reported following administration. Less frequently, gastritis has been observed. Pancreatitis has been reported very rarely.
Immune system Disorders:
Hypersensitivity reactions have been reported following treatment with NSAIDs in patients with, or without, a history of previous hypersensitivity reactions to NSAIDs. These may consist of(a) nonspecific allergic reactions and anaphylaxis (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, or (c) assorted skin disorders, including rashes of various types, pruritis, urticaria, purpura, angiodema and less commonly exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme)
Metabolic and nutrition disorders: Thirst, hyperkalaemia.
Psychiatric disorders: Insomnia, dream abnormalities, depression, confusion and hallucinations
Cardiac disorders: Oedema, angioneurotic edema, peripheral oedema, palpitations, cardiac failure and congestive heart failure have been reported in association with NSAID treatment.
Clinical trial and epidemiological data suggest that use of coxibs and some NSAIDs (particularly at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4).
Vascular disorders: Hypertension, vasculitis.
Other adverse events reported less commonly include:
Hepatobiliary disorders: Abnormal liver function tests, fatal hepatitis and jaundice.
Nervous system disorders: Convulsions, lightheadedness, inability to concentrate and cognitive dysfunction, retrobulbar optic neuritis, headaches, paraesthesia, exacerbation of parkinson's disease, reports of aseptic meningitis (especially in patients with existing auto-immune disorders, such as systemic lupus erythematosus, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting, fever and disorientation (see section 4.4), hallucinations, dizziness, nervousness, euphoria, low temperature and drowsiness.
Blood and lymphatic system disorders: Thrombocytopenia, eosinophilia, leucopenia, neutropenia, agranulocytosis, decreased platelet aggregation, prolonged bleeding time, aplastic anaemia and haemolytic anaemia. decrease in hemoglobin levels and/or hematocrit, granulocytopenia.
Eye Disorders: Corneal opacity, blurred vision, visual disturbances, papillitis and papilloedema.
Ear and Labyrinth disorders: Hearing disturbances including impairment, tinnitus, and vertigo.
Respiratory, thoracic and mediastinal disorders: Dyspnoea, asthma, rhinitis, eosinophilic pneumonitis and pulmonary oedema.
Skin and subcutaneous tissue disorders: Skin rashes including fixed drug eruption, itching (pruritus), urticaria, ecchymoses, purpura, sweating. Alopecia, erythema multiforme, skin eruption, Stevens Johnson syndrome, erythema nodosum, lichen planus, pustular reaction, SLE, epidermal necrolysis, very rarely toxic epidermal necrolysis, photosensitivity reactions (including cases in which skin resembles porphyria cutanea tarda "pseudoporphyria") or epidermolysis bullosa-like reactions which may occur rarely.
If skin fragility, blistering or other symptoms suggestive of pseudoporphyria occur, treatment should be discontinued and the patient monitored.
Musculoskeletal and connective tissue disorders: Myalgia and muscle weakness.
Renal and urinary disorders: Including, but not limited to, glomerular nephritis, interstitial nephritis, nephrotic syndrome, pollakiuria, proteinuria, haematuria, raised serum creatinine, nephropathy, renal insufficiency, renal papillary necrosis and renal failure.
Reproductive system and breast disorders: Female infertility.
General disorders and administration site conditions: Pyrexia, mild peripheral oedema, fatigue and malaise.
Investigations
Elevated transaminases or alkaline phosphatases, elevated bilirubin levels, elevated serum creatinine, increased blood pressure.
4.9 Overdose:
A) Symptoms:
Symptoms include headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, heartburn, drowsiness, dizziness, tinnitus, fainting, occasionally convulsions, transient changes in liver function, hypothrombinemia, apnea and metabolic acidosis. In cases of significant poisoning acute renal failure and liver damage are possible.
B) Therapeutic measure:
Patients should be treated symptomatically as required.
Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. Alternatively, in adults gastric lavage should be considered within one hour of ingestion of a potentially life-threatening overdose.
Good urine output should be ensured.
Hemodialysis does not reduce the plasma concentration of naproxen because of the high protein binding. Renal and liver function should be closely monitored.
Patients should be observed for at least four hours after ingestion of potentially toxic amounts. Frequent or prolonged convulsions should be treated with intravenous diazepam. Other measures may be indicated by the patient’s clinical condition.
Respiratory depression and coma may occur after the ingestion of NSAIDs but are rare.
In one case of naproxen overdose, transient prolongation of the prothrombin time due to hypothrombinaemia may have been due to selective inhibition of the synthesis of vitamin-K dependent clotting factors.
A few patients have experienced seizures, but it is not known whether these were naproxen related or not. It is not known what dose of the drug would be life-threatening Haemodialysis does not decrease the plasma concentration of naproxen because of the high degree of protein binding. However, haemodialysis may still be appropriate in a patient with renal failure who has taken naproxen.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Naproxen is a phenylpropionic acid derivative which has analgesic, anti-inflammatory and antipyretic action. It is used in the treatment of rheumatoid arthritis and other rheumatic or musculo-skeletal disorders, dysmenorrhea and acute gout.
Naproxen inhibits prostaglandin synthetase (as do other NSAIDs). As with other NSAIDs, however, the exact mechanism of its anti-inflammatory action is not known.
5.2 Pharmacokinetic properties:
Naproxen is readily absorbed from the gastro-intestinal tract. Absorption is claimed to be more rapid with the sodium salt (Naproxen sodium). Peak plasma concentration is attained 2 to 4 hours after oral ingestion. Naproxen is present in the blood mainly as unchanged drug. It is extensively bound to plasma proteins and has a half-life of about 15 hours enabling a steady state to be achieved within 3 days of initiation of therapy on a twice daily dose regimen. The degree of absorption is not significantly affected by either foods or most antacids. Excretion is almost entirely via the urine, mainly as conjugated naproxen, with some unchanged drug. Metabolism in children is similar to that in adults. Chronic alcoholic liver disease reduces the total plasma concentration of naproxen but the concentration of unbound naproxen increases. In the elderly, the unbound plasma concentration of naproxen is increased although total plasma concentration is unchanged. About half of the dose is excreted in the urine in 24 hours and about 94% in 5 days largely as the glucuronide. It crosses the placenta and is excreted in breast milk.
5.3 Preclinical safety data
There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.
Carcinogenicity
Naproxen was administered with food to Sprague-Dawley rats for 24 months at doses of 8, 16 and 24mg/kg/day. Naproxen was not carcinogenic in rats.
Mutagenicity
Mutagenicity was not seen in Salmonella typhimurium (5 cell lines), Sachharomyces cerevisisae (1 cell line), and mouse lymphoma tests.
Fertility
Naproxen did not affect the fertility of rats when administered orally at doses of 30mg/kg/day to males and 20mg/kg/day to females.
Teratogenicity
Naproxen was not teratogenic when administered orally at dose of 20mg/kg/day during organogenesis to rats and rabbits.
Perinatal/Postnatal Reproduction
Oral administration of naproxen to pregnant rats at doses of 2, 10 and 20mg/kg/day during the third trimester of pregnancy resulted in difficult labour. These are known effects of this class of compounds and were demonstrated in pregnant rats with aspirin and indometacin.
|
6. |
PHARMACEUTICAL PARTICULARS | ||
|
6.1 |
List of excipients | ||
|
Polyvinylpyrrolidone |
B.P |
34.0 mg | |
|
Lactose |
B.P. |
148.48 mg | |
|
Maize starch |
B.P |
60.8 mg | |
|
Magnesium stearate |
B.P |
1.52 mg | |
|
Sodium starch glycollate |
B.P |
15.2 mg | |
|
Quinoline yellow |
H.S.E |
0.16 mg | |
|
Sunset yellow |
H.S.E |
0.01 mg | |
6.2 Incompatibilities
Not applicable
6.3 Shelf life
4 years
6.4 Special precautions for storage
Store below 25 C. Protect from light and moisture.
6.5 Nature and contents of container
Securitainer with polypropylene lids containing frusemide tablets (material of the container complies to EEC directives for plastic in contact with drugs and food stuff) in the packs of 28’s, 30's, 56’s, 60's, 100's, 250's, 500's.
Blister packs of PVC thickness of 0.25 mm and Aluminium foil of thickness of 20 microns.
6.6 Instructions for use/handling
None
7 MARKETING AUTHORISATION HOLDER
Pharmvit Limited
Unit 13, Metropolitan Centre
Derby Road
Greenford
Middlesex UB6 8UJ
8. MARKETING AUTHORISATION NUMBER
PL 4556/0025
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
4/11/93
10 DATE OF REVISION OF THE TEXT
21/01/2014